Streptococcus pneumoniae is a common bacterium that causes many types of infection other than pneumonia, including acute sinusitis, otitis media, and meningitis. Infection by this bacterium is a significant cause of infant mortality in developing countries, killing more than 3000 people per day, the majority of whom are children below the age of five. Unfortunately, the incidence of strains resistant to penicillin and other antimicrobial agents has been increasing rapidly worldwide since the mid-1990s. Thus, developments of new antibiotics are needed to maintain control of this deadly organism.
The mevalonate pathway (FIG. 1) is an important cellular metabolic pathway present in all higher eukaryotes and many bacteria. Isopentenyl diphosphate, the pathway end-product, is the five-carbon building block used for the biosynthesis of isoprenoids, which in turn lead to many biologically active small molecules, including cholesterol, steroid hormones, and vitamin A. It was discovered that the mevalonate pathway in S. pneumoniae is regulated by 5-diphosphomevalonate (DPM). (See, Leyh, T. S., et al., Biochemistry 2004, 43, 16461.) DPM is a feedback inhibitor of mevalonate kinase (MVK), the first enzyme in the mevalonate pathway, binding tightly to an allosteric site of MVK in S. pneumonia. However, human MVK is not inhibited at DPM concentrations that essentially completely inhibit the streptococcal system. It has also been reported that S. pneumoniae in which the mevalonate pathway is mutated do not survive in mouse lung or serum.
On these bases, it appeared that DPM could be a lead compound for the development of new anti-streptococcal antibiotics that do not interfere with human metabolism. However, the highly-charged diphosphate compounds do not penetrate the cell membrane. Further, phosphatase degradation of the diphosphate also can occur. For these and other reasons, there remains an ongoing search in the art for effective inhibitors of the mevalonate pathway of S. pneumoniae. 